The present invention relates to new compounds, the substantially optically pure levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of the formula 
to a process for the preparation of these compounds and to their use for the preparation of substantially optically pure levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine. The latter compounds, are valuable intermediates for the preparation of substantially optically pure therapeutically active compounds, in the levorotatory and dextrorotatory forms.
These therapeutically active compounds may be used in the treatment of asthma, allergies, inflammation and anxiety, and as sedative or tranquilizing agents. A property frequently observed with these compounds is their high degree of peripheral and/or central antihistaminic activity, as the basis for their use as a drug.
It is well known that the biological properties of many compounds, such as for example drugs, hormones, herbicides, insecticides or sweetening agents, are influenced by stereochemical factors. The importance of the relationships between the optical activity and the biological properties, has been stressed since 1926 (A. R. CUSHNY, Biological.Relations of optically Isomeric Substances, Williams and Williams Co., Baltimore, 1926). Since that time, many examples abound which have confirmed the now generally accepted principle that a racemic compound and its levorotatory and dextrorotatory enantiomers should be considered as entirely distinct pharmacological entities. The optical activity, which is an image of the asymmetrical structure of an organic compound is one of the important factors which govern the pharmacological activity of this compound and its biological response. Indeed, according as to whether the levorotatory or dextrorotatory form of a drug is used, considerable differences in the properties, such as its transport, its distribution in the organism or its elimination can appear. These properties are decisive for the concentration of the drug in the organism or its exposure time at the site of activity. Furthermore, the pharmacological activity of the two isomers can differ considerably. For example, one enantiomer may be much more active than the other or, in a border-line case, this enantiomer could possess alone all the pharmacological activity, the other being totally inactive and serving only as a simple diluent. It can also occur that the pharmacological activities of the two isomers are different, which produces consequently two compounds having distinct therapeutic properties. Moreover, the metabolism and the toxicity can be very different from one isomer to another, so much so that one of the optically active isomers can be more toxic than the other. One of the most striking examples in this field is that of thalidomide, where the two enantiomers possess similar hypnotic effects but only the S enantiomer has teratogenic effects.
Finally, it has also to be added that the optical isomers are useful as probes which are of uttermost importance in the study of chemical interactions with physiological mechanisms (for example, the selectivity of binding to a receptor).
That is the reason why many pharmaceutical laboratories devote much time and efforts to isolate or synthesize the enantiomers of pharmacologically active compounds and to study the therapeutic properties thereof.
A process for the preparation of the enantiomers of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride, known as a non-sedative antihistamine drug under the generic name of cetirizine, is described in British Patent No. 2,225,321. This process is based on the use of levorotatory or dextrorotatory 1-[(4-chlorophenyl)phenylmethyl]piperazine as starting material. In that patent, the enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine are obtained by chemical resolution of the racemic form, using conventional methods, in particular, by salt formation with a suitably selected optical isomer of tartaric acid.
The major disadvantages of this process are, on the one hand, that the yield of the resolution step of the racemic 1-[(4-chlorophenyl)phenylmethyl]piperazine is extremely low (only 12.7%) and, on the other hand, that the optical purity of the dextrorotatory and levorotatory enantiomers so obtained is insufficient and does not allow the final product to be prepared with an optical purity greater than 95%.
Consequently, it appears to be very desirable to provide new routes for preparing the enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine with improved optical purity and in better yields and, thereby, to provide excellent starting materials to produce optically active isomers of useful drugs with a very high degree of optical purity.
But, to achieve this object, it is necessary to find precursors having already the correct stereochemical configuration and which, on the one hand, can be themselves prepared relatively simply and economically with satisfactory optical purity, and, on the other hand, which can be converted easily and with high yields into the substantially optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine.
We have now discovered a new compound, 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine, the levorotatory and dextrorotatory forms of which comply perfectly with this object.
Accordingly, the present invention provides as new compounds, the levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of the formula 
According to the present invention, the enantiomers of the compound of formula I are advantageously in a substantially optically pure form.
In the present specification, by xe2x80x9csubstantially optically purexe2x80x9d, is meant an optical purity greater than 98% and this optical purity corresponds to the percent excess of the optically active isomer present in major amount with respect to the optically active isomer present in minor amount, and determined by high performance liquid phase chromatography (HPLC) on a chiral stationary phase.
This optical purity can be defined by the equation described on page 107 of the book of J. MARCH, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, John Wiley and Sons, Inc., New York, 3rd Edition, 1985:       Optical purity (in %)    =                              [                      (            +            )                    ]                -                  [                      (            -            )                    ]                                      [                      (            +            )                    ]                +                  [                      (            -            )                    ]                      xc3x97    100  
Where
[(+)]=concentration of the dextrorotatory enantiomer; and
[(xe2x88x92)]=concentration of the levorotatory enantiomer.
The present invention further relates to a process for preparing the levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of formula I, which comprises reacting an enantiomer of (4-chlorophenyl)phenylmethylamine of the formula 
with a N,N-diethyl-4-methylbenzenesulfonamide of the formula 
wherein X is a chlorine, bromine or iodine atom or the (4-methylphenyl)sulfonyloxy or methylsulfonyloxy group, in the presence of 2.2 to 4.4 equivalents of an organic or inorganic base per equivalent of the enantiomer of (4-chlorophenyl)phenylmethylamine and at the boiling point of the reaction mixture.
Bases suitable for use to prepare compounds of formula I include organic bases such as ethyldiisopropylamine, N-ethylmorpholine, 2,4,6-trimethylpyridine or triethylamine, preferably ethyldiisopropylamine, and inorganic bases such as sodium carbonate.
The levorotatory and dextrorotatory enantiomers of (4-chlorophenyl)phenylmethylamine of formula II, used as starting materials are known compounds; they can be prepared by chemical resolution of racemic (4-chlorophenyl)phenylmethylamine by known methods using tartaric acid. These enantiomers can be prepared with an optical purity of at least 98%.
The compounds of formula III used as starting materials are also known products which can be easily obtained starting from bis(2-hydroxyethyl)amine and using known methods.
The present invention further relates to the use of the new levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of formula I, for the preparation of the substantially optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine of the formula 
According to the present invention, the levorotatory and dextrorotatory enantiomers of the compound of formula IV are prepared by a process, which comprises subjecting an enantiomer of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of formula I to hydrolysis with hydrobromic acid, in acetic acid medium and in the presence of a phenolic compound, preferably 4-hydroxybenzoic acid.
This hydrolysis is generally carried out at a temperature of between 18 and 100xc2x0 C., preferably at a temperature of about 25xc2x0 C.
The advantages resulting from the use of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of formula I, in the form of its levorotatory or dextrorotatory enantiomers according to the invention, are numerous.
These advantages appear not only at the level of the route which leads to the enantiomers of the compound of formula I but also at the level of the conversion step of these enantiomers to prepare the substantially optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine of formula IV.
First of all, we have found that the enantiomers of the compound of formula I, with a 4-methylphenylsulfonyl group on the amine function, were practically the sole capable of being synthesized in a wholly satisfactory manner. Indeed, if, in the preparation of these compounds, it is attempted to replace the N,N-diethyl-4-methylbenzenesulfonamide of formula III by a corresponding compound, in which the 4-methylphenylsulfonyl group has been replaced by hydrogen or by another protecting group of the amine function such as for example a carbonyl, alkyl or triphenylmethyl group, an important racemization of the starting compound of formula II and/or of the compound of formula I, or the production of many undesirable by-products, is observed during the formation of the enantiomer of the compound of formula I.
Moreover, the starting materials of formula III, wherein the 4-methylphenylsulfonyl group would have been replaced by hydrogen, are known to be extremely toxic due to the presence of a free amine group (nitrogen mustards).
However, all of these significant disadvantages can be avoided by using the N,N-diethyl-4-methylbenzenesulfonamide of formula III, as starting material. Indeed, the enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of formula I, according to the invention, are prepared by a process which does not cause racemization and provides a high yield, which can reach 89%, and these enantiomers are obtained with an optical purity greater than 98% which, in many cases, approaches 100%, using sulfonated raw materials of relatively low toxicity and much less hazardous to manipulate. This last point means also a considerable advantage as regards the industrial application of the process according to the invention.
Moreover, the use of the enantiomers of the compound of formula I is particularly advantageous for the preparation of the enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine of formula IV. Indeed,
on the one hand, the enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine of formula IV are obtained with a yield much greater than 80%. This yield is considerably higher than that achievable using the process described in British patent No. 2,225,321;
on the other hand, since the hydrolysis reaction, leading to the formation of the enantiomers of the compound of formula IV, is non-racemizing, these enantiomers are obtained with an optical purity which is much greater than 95%, even approaching 100%.
The enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of formula I, according to the invention, thus, open up a highly favorable preparative route to the enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazines of the formula IV.
The substantially optically pure levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine of formula IV, so prepared, are of interest mainly as precursors in the preparation of substantially optically pure therapeutically active levorotatory and dextrorotatory form of 1[(4-chlorophenyl)phenylmethyl]piperazines of the formula 
wherein R is a methyl, (3-methylphenyl)methyl, (4-tert-butylphenyl)methyl, 2-(2-hydroxyethoxy)ethyl, 2-[2-(2-hydroxyethoxy)ethoxy]ethyl, 2-(carbamoylmethoxy)ethyl, 2-(methoxycarbonylmethoxy)ethyl or 2-(carboxymethoxy)ethyl radical.
These compounds, which are already known in the racemic form, possess valuable pharmacological properties and may be used for the treatment of asthma, allergies and inflammation or as sedative, tranquilizing or anxiolytic agents.
The preferred compounds of formula V are the levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-methylpiperazine, of 1-[(4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine, of 1-[(4-tert-butylphenyl)methyl]-4-[(4-chlorophenyl)phenylmethyl]piperazine, of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethanol, of 2-[2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethoxy]ethanol, of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide, of methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate and of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid and the pharmaceutically acceptable salts of these enantiomers.
The preparation of these substantially optically pure enantiomers can be carried out by means of known methods which comprise reacting an enantiomer of the compound of formula IV, while hot, with a halide of the formula RX wherein R has the meaning given above and X represents a halogen atom. The enantiomers of formula V are new compounds, with the exception of the compounds where R is a 2-(carboxymethoxy)ethyl radical, and possess valuable antihistaminic properties; in particular, they exhibit a very distinct difference in behavior as regards the inhibition of the histamine H1 receptor, one of the enantiomers being a competitive inhibitor and the other a non-competitive inhibitor.
The pharmacological tests described below demonstrate these properties.